Device for in-vivo determination of eye moisture

ABSTRACT

A medical diagnostic device and method, the device including: (a) an alternating current source, adapted to produce an alternating current; (b) an electrode arrangement having at least first and second electrodes, separated by an electrically insulating region, the arrangement having an at least semi-rigid region that fixes the electrodes in a spaced-apart manner, the arrangement adapted to contact the soft tissue on the inner surface of the eyelid; and (c) a processor, associated with the electrode arrangement, said electrodes electrically connected to the alternating current source; wherein, when the electrode arrangement is provided with the alternating current, and is disposed against the soft tissue, the soft tissue electrically bridges between the electrodes to form an electrical circuit, wherein an electrical signal is produced by the alternating current electrically passing between the electrodes via the soft tissue; wherein the processor is adapted to receive in-vivo based electrical information originating from the electrical signal, via the circuit, and to produce an output relating to, or derived from, the moisture parameter, based on the in-vivo electrical information; and wherein the processor is designed and configured to compute the moisture parameter in the soft tissue, at least partially based on the in-vivo electrical information, and based on an empirical correlation between the in-vivo electrical information and the moisture parameter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT/IB2013/000173 titled““Device for In-Vivo Determination of Eye Moisture” and filed on oraround Feb. 12, 2013, which is incorporated herein by reference in itsentirety. This application draws priority from UK Patent Application No.GB1202387.5, entitled “Device for In-Vivo Determination of EyeMoisture”, and filed Feb. 12, 2012, which application is herebyincorporated by reference for all purposes as if fully set forth herein.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to an instrument for indirectlydetermining the moisture of soft tissue on an inner surface of an eyelidof a patient.

Dry eye is recognized as a disturbance of the Lachrymal Functional Unit,a system made up of the lachrymal glands, the ocular surface (cornea,conjunctiva and meibomian glands) and lids. This system further includesthe sensory and motor nerves that connect these components.

The dry eye phenomenon may result from inadequate tear production: thelachrymal gland fails to produce sufficient tears to keep theconjunctiva and cornea covered by a complete tear layer. The dry eyephenomenon may also stem from an abnormal tear composition, which causesan overly rapid evaporation of the tears. Thus, while the tear glandproduces a sufficient amount of tears, the rate of evaporation is suchthat the entire surface of the eye cannot be kept covered with acomplete layer of tears in various activities or environments.

Various means have been disclosed for diagnosing dry eye, or moregenerally, the extent of moisture in the outer eye. Schirmer's testdetermines whether the eye produces enough tears to keep it moist. Paperstrips, inserted in an outer region of the eye (typically the lowereyelid), absorb the tear liquid. After several minutes, the amount ofliquid absorbed is measured. Based on the amount of liquid absorbed, adetermination may be made regarding the dryness of the eye. Thediagnostic reliability of Schirmer's test has been the subject ofscholarly debate, and many believe that the test may systematicallyproduce false “normal” results.

In-vitro tear osmolarity, which indicates the concentration of saltsdissolved in the tear, has long been correlated with dryness of the eye.Since the 1970's, increasing severity of eye dryness has been correlatedwith increasing in-vitro tear osmolarity (see Farris R L, “Tearosmolarity—a new gold standard?” Adv Exp Med Biol 1994; 350:495-503).

Over the years, various techniques and systems have been developed forremoving tear liquid from the eye, and for subjecting the liquid toin-vitro analysis. An exemplary commercial product is the TearLab™Osmolarity system (see Dr. G. N. Foulks et al., “TearLab™ Osmolarity asa Biomarker for Disease Severity in mild to Moderate Dry Eye Disease”,www.bon.de/download/tearlab/Summary_poster_2009_AAO.pdf). The system isadapted to measure the osmolarity of human tears for diagnosing dry eyedisease. The tear liquid is collected directly from the inferior lateraltear meniscus. A single-use, disposable polycarbonate microchip containsa microchannel at the tip, designed to collect 50 nanoliters (nL) oftear fluid directly from the inferior meniscus of the ocular surface.Gold electrodes embedded in the polycarbonate card enable in-vitromeasurement of the electrical impedance of the tear fluid sample in thechannel. The measured impedance is correlated to eye dryness, and tomeasured eye dryness parameters of Schirmer's test and other diagnosticmeasurement methods for determining dry eye.

Table 1 of Foulks et al., provided as Table 1 hereinbelow, shows typicalvalues for various eye dryness diagnostic methods, as a function ofseverity—Grade 0 to Grade 4, with Grade 4 representing the highestseverity of dry eye disease.

TABLE 1 Grade 0 1 2 3 4 Schirmer Test (mm) 35 7 5 2 0 TBUT (seconds) 457 5 3 0 Staining (NEI/Industry scale) 0 3 8 12 20 OSDI 0 15 30 45 100Meibomian Grading Score 0 5 12 20 28 Osmolarity (mOsms/L) 275 308 324364 400It is intuitively evident that in Schirmer's Test, tear absorptionlength would be expected to decrease with increasing severity of dry eyedisease. Table 1 demonstrates this trend. Similarly, it would beexpected that the degree of salinity, or osmolarity, of the tear liquidwould increase with increasing severity of dry eye disease. Table 1 alsodemonstrates this trend.

Foulks et al., statistically derive an equation correlating osmolarityand severity of eye dryness. On a scale of 0 to 1 (where 1 representsthe highest level of severity), the correlation equation is given as:

SEVERITY=(y−275)/125

where y is the osmolarity in units of mOsms/L. It is clear from Table 1and from the correlation equation, that increasing osmolarity isindicative of increasingly severe eye dryness.

U.S. Pat. No. 4,996,993, filed Dec. 7, 1988, discloses several devicesfor determining in-vivo tear osmolarity in the open eye. A first device,an osmometer, is adapted to measure the osmolarity of a bodily fluidsuch as tears or sweat, and includes a detachable probe in combinationwith means for measuring the conductivity between two electrodes of theprobe. The osmometer further includes means for converting the measuredvalue of conductivity of the in-vivo sample into a corresponding valueof osmolarity and display means for displaying a visible representationof that value.

A second device is adapted to measure, by means of a sensor, somephysical quantity (such as dew point temperature) related to the vaporpressure from a bodily fluid. The device is mounted inside a confining,generally concave shell placed adjacent to a portion of the human bodyfor a measurement to be made. To measure tear osmolarity in the openeye, the confining shell could take the form of a conventional eyecup.The sensor can be a thermocouple or thermistor controlled by amicroprocessor to measure vapor pressure by the dew point depressionmethod.

U.S. Pat. No. 4,996,993 fails to explicitly disclose the basis forconverting the measured value of conductivity of the in-vivo sample intoa corresponding value of osmolarity. However, in studying U.S. Pat. No.4,996,993, one of ordinary skill in the art would appear to derive someguidance from that patent's reference to a relevant journal article, andto the patent's treatment thereof:

-   -   The particular pathologic condition designated “dry eye” and its        connection to tear film osmolarity is described in the article        “Osmolarity of Tear Microvolumes in Keratoconjunctivitis Sicca,”        by Jeffrey P. Gilbard et al., in Arch. Ophthalmol., Vol. 96,        April, 1978, pages 677-681. When the surface of the eye starts        to dry out the tear film becomes hypertonic (elevated        osmolarity), causing discomfort and epithelial damage.        Thus, although U.S. Pat. No. 4,996,993 fails to provide an        explicit relationship between in-vivo measurement of        conductivity and tear liquid osmolality, it is fairly understood        that higher conductivity (or lower impedance) measurements are        correlated with eye dryness, as taught by Gilbard et al., the        above-referenced Farris article (which also references and        supports the findings of Gilbard), and as confirmed and detailed        in the recent study of Foulks et al., referenced above.

In “Electrical conductivity of tear fluid in healthy persons andkeratoconjunctivitis sicca patients measured by a flexibleconductimetric sensor” [Graefe's Arch Clin Exp Ophthalmol (1996)234:542-546], Ogasawara et al. disclose a flexible conductimetric sensorthat is small enough and flexible enough to be placed on the ocularsurface to measure the electrical conductivity of tear fluid in vivo.The sensitive area of the sensor was placed within the lower temporalconjunctival cul-de-sac. The conductivity was measured continuously formore than 30 seconds. The sodium chloride concentration of tear fluidswas calculated from a calibration curve relating electrical conductivity(Siemens) to the NaCl concentration (g/l), and converted to theequivalent electrolyte concentration.

The average electrolyte concentration of 33 samples obtained from 17healthy persons was 296.4 mEq/l. The electrolyte concentration in 29samples obtained from keratoconjunctivitis sicca patients averaged 324.8mEq/l. The difference was found to be statistically significant.

The above-described advances notwithstanding, the present inventor hasrecognized a need for improved, patient-friendly, cost-effective devicesand methods for evaluating the moistness or dryness in the vicinity ofthe outer eye, and the subject matter of the present disclosure andclaims is aimed at fulfilling this need.

SUMMARY OF THE INVENTION

According to the teachings of the present invention there is provided adevice for evaluation of a moisture parameter associated with moistureof soft tissue on an inner surface of an eyelid of a subject, the deviceincluding: (a) an alternating current source, adapted to connect to apower supply and to produce an alternating current; (b) an electrodearrangement having at least a first electrode and a second electrode,the first electrode electrically separated from the second electrode byan electrically insulating region, the arrangement having an at leastsemi-rigid region that fixes the electrodes in a spaced-apart manner,the arrangement adapted to contact the soft tissue on the inner surfaceof the eyelid, the electrodes and the insulating region composed ofbiocompatible materials, and (c) a processor, associated with theelectrode arrangement, the first and second electrodes beingelectrically connected to the alternating current source; wherein, whenthe electrode arrangement is provided with the alternating current, andis disposed against the soft tissue, the soft tissue electricallybridges between the electrodes to form an electrical circuit, wherein anelectrical signal is produced by the alternating current passing fromthe first electrode to the second electrode via the soft tissue, whereinthe processor is adapted to receive in-vivo based electrical informationoriginating from the electrical signal, via the circuit, and to producean output relating to, or derived from, the moisture parameter, based onthe in-vivo electrical information, and wherein the processor isdesigned and configured to compute the moisture parameter in the softtissue, at least partially based on the in-vivo electrical information,and based on an empirical correlation between the in-vivo electricalinformation and the moisture parameter.

According to another aspect of the present invention there is provided amethod for evaluating a parameter associated with moisture of softtissue of an inner eyelid of a subject, the method including: (a)providing a device including: (i) an alternating current source, adaptedto connect to a power supply and to produce an alternating current; (ii)an electrode arrangement having at least a first electrode and a secondelectrode, the first electrode electrically separated from the secondelectrode by an insulating region, the arrangement having an at leastsemi-rigid region that fixes the electrodes in a spaced-apart manner,the arrangement adapted to contact the soft tissue of the inner eyelidof the subject, (iii) a processor, associated with the electrodearrangement; wherein the first and second electrodes are electricallyconnected to the alternating current source, (b) disposing a portion ofthe electrode arrangement on the inner eyelid, against the soft tissue,wherein the soft tissue electrically bridges between the electrodes toform an electrical circuit, (c) passing the alternating current from thefirst electrode to the second electrode via the soft tissue, producingan electrical signal; (d) receiving, by the processor, electricalinformation originating from the electrical signal, via the circuit, and(e) computing, by the processor, a representation of the parameterassociated with the moisture of the soft tissue, based on the electricalinformation.

According to yet another aspect of the present invention there isprovided a method for evaluating a parameter associated with moisture ofsoft tissue of an inner eyelid of a subject, the method including (a)providing a device substantially as described herein; (b) disposing aportion of the electrode arrangement on the inner eyelid, against thesoft tissue such that the soft tissue electrically bridges between theelectrodes to form said electrical circuit; (c) passing said alternatingcurrent from said first electrode to said second electrode via the softtissue, to produce said electrical signal; and (d) receiving, by saidprocessor, said electrical information originating from said electricalsignal, via said circuit.

According to further features in the described preferred embodiments,the method further includes computing, by said processor, the parameter,or a representation of the parameter, associated with the moisture ofthe soft tissue, based on the in-vivo electrical information, and basedon an empirical correlation between the electrical information and themoisture parameter.

According to still further features in the described preferredembodiments, the empirical correlation includes an inverse relationshipbetween the electrical impedance derived from the electrical signal orfrom the in-vivo electrical information, and the moisture parameter,such that an increasing level of moisture of soft tissue on the innersurface of the eyelid is correlated with a decreasing of the electricalimpedance.

According to still further features in the described preferredembodiments, the empirical correlation includes a direct relationshipbetween an electrical conductivity derived from the electrical signal orfrom the in-vivo electrical information, and the moisture parameter,whereby an increasing level of moisture of soft tissue on the innersurface of the eyelid is correlated with a decreasing of the electricalconductivity.

According to still further features in the described preferredembodiments, the in-vivo electrical information consists of measuredin-vivo electrical information.

According to still further features in the described preferredembodiments, the device further includes a display, electricallyassociated with the processor, and adapted to display the output.

According to still further features in the described preferredembodiments, the device further includes an adaptor, electricallyconnected to the alternating current source, the adaptor having anengagement mechanism adapted to physically hold a portion of thearrangement and to electrically connect the arrangement to the currentsource and to the processor.

According to still further features in the described preferredembodiments, the engagement mechanism is adapted to releasably andreversibly engage the arrangement.

According to still further features in the described preferredembodiments, the arrangement includes, or consists of, an electrodestick.

According to still further features in the described preferredembodiments, the electrode stick is an elongated stick having a firstend adapted to be received by the engagement mechanism, and a second endhaving the electrodes.

According to still further features in the described preferredembodiments, the second end has a maximum width of 6.5 mm, 6.3 mm, 6.2mm, or 6 mm.

According to still further features in the described preferredembodiments, the second end has a minimum width of 2 mm.

According to still further features in the described preferredembodiments, the maximum distance between the second end of the stick,and an end of the electrodes distal to the second end, is 2.5 mm, 2.2mm, 2 mm, 1.9 mm or 1.8 mm.

According to still further features in the described preferredembodiments, the device further includes an analog-to-digital conversionunit, electrically connected to the electrical circuit, and adapted toconvert the electrical signal from an analog form to a digital form.

According to still further features in the described preferredembodiments, the device further includes a display, electricallyassociated with the processor, and adapted to display the moistureparameter.

According to still further features in the described preferredembodiments, the device further includes a capacitor, electricallydisposed between the electrode arrangement and the processor, thecapacitor having a capacitance to pass an output signal to theprocessor, when the electrical signal is above a pre-defined threshold.

According to still further features in the described preferredembodiments, the end of the electrode arrangement has an attachmentgeometry that is complementary to an attachment geometry of theengagement mechanism.

According to still further features in the described preferredembodiments, the electrodes are disposed on an at least semi-rigidsubstrate.

According to still further features in the described preferredembodiments, the thickness of the electrode arrangement, including thesubstrate, is less than 1.5 mm, less than 1.2 mm, less than 1.0 mm, lessthan 0.8 mm, or less than 0.6 mm.

According to still further features in the described preferredembodiments, the moisture parameter is, or includes, an eye-moisturecharacterization parameter selected from the group of parametersconsisting of a calculated in-vitro osmolarity, a calculated Schirmer'sTest absorption length, a calculated Meibomian Grading Score, an ocularsurface disease index (OSDI), a corneal and conjunctival stainingresult, and an eye dryness severity value.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice. Throughout thedrawings, like-referenced characters are used to designate likeelements.

In the drawings:

FIG. 1 is a perspective view of one aspect of the in-vivo eye moisturedetermination device, according to the present invention;

FIG. 2 shows the inventive device being used to make an in-vivo eyemoisture determination, the electrode stick being contacted with themoist tissue of the inner eyelid;

FIG. 3 is an exemplary graph plotting measured Schirmer's Testabsorption depth as a function of in-vivo measured impedance;

FIG. 4A provides (1): a graph plotting in-vitro measured impedance ofsolutions as a function of NaCl concentration, based on Ogasawara etal.; and (2) an exemplary graph plotting in-vivo measured impedance ofsolutions, using a device and method of the present invention, as afunction of the correlated NaCl concentration;

FIG. 4B is an exemplary graph plotting calculated in-vitro osmolarity asa function of in-vivo measured impedance;

FIG. 5 is a schematic block diagram of one aspect of the in-vivo eyemoisture determination device, according to the present invention;

FIG. 6a is a schematic block diagram of an electrode arrangement orstick, according to one embodiment of the present invention;

FIG. 6b provides a schematic, perspective view of the electrode stick ofFIG. 6a , disposed, at one end, within a receptacle of the inventivedevice; and

FIG. 7 is a logical flow diagram showing one aspect of the method of thepresent invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

The principles and operation of the inventive instrument for evaluatingthe moistness or dryness in the vicinity of the outer eye may be betterunderstood with reference to the drawings and the accompanyingdescription.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

Referring now to the drawings, FIG. 1 is a perspective view of oneaspect of an in-vivo eye moisture determination device 100, according tothe present invention. From a first end of an elongated housing 101extends a receptacle or adaptor 125 for physically and electricallyreceiving an electrode stick (shown in FIG. 2, and shown schematicallyin FIG. 6b ). At a distal end of housing 101 may be disposed a batteryor power source 104. A switch 128 may advantageously be disposed on afacing of housing 101, for facile activation and deactivation of device100. An electrode stick switch 129 for locking and releasing the stickfrom adaptor 125 may similarly be disposed on a facing of housing 101.

In describing an in-vivo, conductivity-based device for assessing eyedryness, U.S. Pat. No. 4,996,993 teaches that the “distal ends 24A and24B of electrodes 26 and 28, respectively, end in blunt shapes suitablefor touching delicate parts of the body such as the cornea”. I havefound, however, that directly contacting an electrical probe with thecornea raises patient safety issues. The measurements made may beunreliable, due to poor contact conditions, and the low amount of liquidnatively disposed on the cornea. The impact on reliability of voluntaryand involuntary motions of the patient, due to pain, discomfort, orapprehension, cannot be underestimated. Moreover, such unreliableresults may be made even less reliable by the procedures used by eachparticular medical personnel operating the conductivity-based device,and by their medical concerns pertaining to causing damage to thesensitive and delicate regions of the eye.

I have also found that disposing an electrical probe within the lowertemporal conjunctival cul-de-sac, as taught by Ogasawara et al., mayraise various patient safety issues. Some of these issues may be evenmore severe in view of the lengthy measuring time of more than 30seconds.

FIG. 2 shows the inventive device being used to make an in-vivo eyemoisture determination, the electrode stick being contacted with themoist tissue of the inner eyelid. It will be appreciated that thereexists a finite and significant distance between the end of theelectrode stick and the delicate outer surface of the eye, which enablesmedical personnel to practice the procedure of the instant invention ina safe and substantially repeatable fashion.

However, I have found that having a safe and substantially repeatabletesting procedure, while being necessary, may be insufficient inobtaining repeatable and physically meaningful results.

I tested electrode sticks of various widths on the inner surface of thelower eyelid of a particular subject. The results are provided in Table2. The widest stick, 8 mm did not display good repeatability. This maybe attributed to large and varying areas of the electrode that are notfully immersed in the tear liquid. The stick having an intermediatewidth of 6.2 mm displayed improved repeatability. However, the electrodestick having a width of 3.9 mm exhibited, by far, the best repeatabilityperformance.

Thus, the electrode sticks of the present invention may have a width ofat most 6.5 mm, at most 6.3 mm, at most 6 mm, at most 5.7 mm, at most5.5 mm, at most 5.25 mm, at most 5 mm, or at most 4.75 mm. It may bepreferable for the width to be at most 4.5 mm, at most 4.25 mm, or atmost 4.0 mm.

TABLE 2 Trial No. 8 mm 6.2 mm 3.9 mm 1 2.56 3.79 5.20 2 2.78 3.90 5.21 33.59 3.50 5.29 4 error 4.23 5.15 5 5.66 4.44 5.17

Various considerations including practical considerations, may dictate,or at least indicate, a minimum stick width of 2 mm, 2.25 mm, or 2.5 mm.

We have further found that the soft tissue on the inner surface of theeyelid, and more practically, on the inner surface of the lower eyelid,displays an electrical behavior having both a resistance component and acapacitance component. Direct current is suitable for measuring theresistance component, but may be unsuitable for measuring thecapacitance component. However, an alternating current source issuitable for measuring both the resistance component and the capacitancecomponent. The frequency of the alternating current source is preferablybetween 100-15,000 Hz, more preferably, between 300-10,000 Hz, and mostpreferably, between 500-5,000 Hz.

Using such an alternating current source, we tested the in-vivoimpedance on the inner surface of the lower eyelid of subjects having avarying degree of eye moisture. These individuals were further subjectedto a conventional Schirmer's Test in the same eye. The results areprovided in Table 3, and are graphically displayed in FIG. 3.Surprisingly, we observe an increase in-vivo measured impedance withdecreasing eye moisture (as physically measured by Schirmer's Test, andas correlated with in vitro osmolality and with the corresponding NaClconcentration). We have found the correlation of increasing in-vivomeasured impedance with decreasing eye moisture to be repeatable.Moreover, this correlation runs opposite and contrary to thewell-established, above-described and referenced correlation betweenincreasing in-vitro measured impedance (decreasing electricalconductivity) and increasing eye moisture.

TABLE 3 Measured Schirmer's Test: Correlated² In-Vivo MeasuredCorrelated¹ NaCl Impedance Absorption Osmolality Concentration(kiloohms) (mm) (mOsms/L) (g/L) 3.6 35 275 8.61 5.1 20 5.4 15 6.7 12 6.57 8.6 2 9.2 1 11 0 400 12.684 ¹Foulks, et al. ²based on Horatio PapaPh.D.: USP29, page 2718(http://www.pharmacopeia.cn/v29240/usp29nf24s0_c785.html#usp29nf24s0_c785-t1)

In FIG. 4A is provided a graph plotting in-vitro measured impedance ofsolutions as a function of sodium chloride concentration, based on dataof the prior art (Ogasawara et al.). FIG. 4A further provides anexemplary graph plotting in-vivo measured impedance of solutions, usinga device and method of the present invention, as a function of thecorrelated sodium chloride concentration.

It is manifest from FIG. 4A that the correlation of eye moisture toimpedance, using the device and method of the present invention,displays a higher sensitivity to impedance than the correlation of theprior art devices and methods. Perhaps more importantly, the correlationis—surprisingly—reversed.

Without wishing to be limited by theory, I believe that the decreasingeye moisture with increasing in-vivo measured impedance may at leastpartly be attributed to liquidless areas or pockets in the inner surfaceof the eyelid. As the eye becomes increasingly dry, such pockets take upan increasing fraction of the surface area of the electrodes, and reduceelectrical conductivity/increase impedance. This phenomenon more thancompensates for the increased conductivity/decreased impedance resultingfrom the higher salinity of the tear liquid in dry eyes.

I believe it is highly surprising that the in-vivo measured impedanceexhibits an inverse behavior with respect to in-vitro measuredimpedance, as a function of eye moisture. I believe it is furthersurprising that the in-vivo measured impedance levels are sufficientlyrepeatable, for a given extent of eye moisture, to enable in-vivoimpedance to be used as a marker for eye moisture determination,particularly in view of the decreased impedance resulting from thehigher salinity of the tear liquid in dry eyes.

The in-vivo measured impedance results may be correlated to any knownmeasure, qualitative or quantitative, of eye moisture or eye dryness,including in-vitro osmolarity or osmolality, Schirmer's Test, MeibomianGrading Score, ocular surface disease index (OSDI), corneal andconjunctival staining, various eye dryness severity scales. Theseresults produce calculated correlations, much as Foulks et al. producecorrelation equations to calculate, from measured in-vitroimpedance/osmolarity, equivalent eye dryness values using other eyedryness determination methods.

In FIG. 4B is provided an exemplary graph plotting calculated in-vitroosmolarity as a function of in-vivo measured impedance.

FIG. 5 is a schematic block diagram of one aspect of a device such asmoisture-analyzing device 100, according to the present invention.Moisture-analyzing device 100 includes a current source such asalternating current source 102, connected to a power supply 104 andadapted to produce an alternating current, and an electrode arrangement110 having at least a first electrode 112 and a second electrode 114 setapart at a fixed distance. First electrode 112 is electrically separatedfrom second electrode 114 by an insulating region 120 having a specificelectrical resistivity of at least 1.0 ohm cm, and more typically, atleast 10⁴ ohm cm or even 10⁶ ohm cm. Presently preferred materials forinsulating region 120 include various biocompatible materials, includingpolymeric materials such as polypropylene and polycarbonates.

Electrode arrangement 110 has a first lead 122 from first electrode 112and a second lead 124 from second electrode 114, first lead 122 beingelectrically connected to alternating current source 102. Electrodearrangement 110 may advantageously be connected to alternating currentsource 102 by means of an adaptor or receptacle 125, which will bedescribed in greater detail hereinbelow.

Electrode arrangement 110 is also electrically connected to a processor,such as central processing unit (CPU) 150. CPU 150 is adapted to receiveelectrical information originating from the electrical signal, via anelectrical circuit 190, and to compute a representation of the level ofmoisture (or severity of dryness) in the soft tissue of the inner eyelidof the subject, based on the electrical information. To this end, avoltage-measuring device, such as voltmeter 156, may advantageously bedisposed on circuit 190, or within processor 150, to measure a voltageof the electrical signal or information.

Second lead 124 may be electrically disposed between second electrode114 and CPU 150. Both current source 102 and second electrode 114 may beconnected to a ground 128.

Within, or otherwise electrically associated with CPU 150, may beprovided a memory unit 151 adapted to store data, e.g., data pertainingto electrical parameters, to individual or collective patient parametersor history, etc. Electrically associated with CPU 150 may be a displayunit 152 and an input unit 154. Display unit 152, which may be ofvarious types known in the art, including LED and LCD displays, maydisplay an output from CPU 150, such as a calculated impedance betweenfirst electrode 112 and second electrode 114, or a correlated level ofmoisture or dryness in the outer vicinity of the subject's eye. Thiscorrelated level may be expressed as the calculated in-vitro osmolality(or osmolarity) equivalent, the calculated Schirmer's test equivalent,calculated eye-dryness severity scale (0 to 4, 0 to 1, etc.), or anyother moisture-related or dryness-related expression that would be knownto one of ordinary skill in the art.

Input unit 154 may be of various types known in the art, and may be usedto select display options, and to provide information to CPU 150. Suchinformation may include data on a particular patient undergoing thetest, or the identity of the particular patient.

Electrode arrangement 110 may also be electrically connected to acapacitor 130, which serves to filter currents that are below apre-determined threshold. A filter such as low pass filter 140 may alsobe electrically connected to capacitor 130, to filter currents that areabove a pre-determined threshold.

The electrical signal from electrode arrangement 110 may be an analogsignal, which is converted to a digital signal by means of ananalog-to-digital (A2D) converter 145. (A2D) converter 145 may bedisposed within CPU 150, or outside CPU 150, as shown. The digitalsignal is then provided to a processing unit of CPU 150.

When electrode arrangement 110 is disposed against soft tissue on aninner surface of the eyelid, the soft tissue electrically bridgesbetween the electrodes to complete electrical circuit 190. The resultingoutput signal is provided to CPU 150 via electrical circuit 190.

Preferably, the current source of electrical circuit 190 is analternating current source such as alternating current source 102.

A secondary, control circuit 195, may be advantageous in controlling theparameters of alternating current source 102 within working limits.Secondary circuit 195 may include CPU 150 and alternating current source102, along with a low pass filter 160 and a resistor 170 disposedtherebetween, to facilitate correction and control of alternatingcurrent source 102 by CPU 150.

FIG. 6a is a schematic top view of a preferred embodiment of electrodestick or electrode arrangement 110. Electrode arrangement 110 mayinclude a thin, at least semi-rigid substrate 232, typically in the formof a stick or plate, for carrying electrodes 112, 114. It may beadvantageous for substrate 232 to exhibit flexibility, at least along awide face thereof, so as to substantially conform to an inner surface ofthe eyelid. However, insulating region 120 must be sufficiently rigid tomaintain the electrodes in a substantially fixed, spaced-apart position.

Presently preferred materials for substrate 232 include variousbiocompatible materials, including polymeric materials such aspolypropylene and polycarbonates.

Electrodes 112, 114 are advantageously made of a highly conducting,biocompatible material such as gold, platinum, copper, silver, as wellas various alloys and mixtures containing such materials.

Receptacle 125 may both mechanically and electrically connect electrodearrangement 110 to alternating current source 102. FIG. 6b provides aschematic perspective view of electrode arrangement 110 and receptacle125 according to an exemplary, preferred embodiment. A first end 234 ofsubstrate 232 engages with an engagement surface of receptacle 125. InFIG. 6b , first end 234 of substrate 232 is received by the engagementsurface, which may be substantially complementary to at least a portionof first end 234. A portion of the engagement surface may exert apressure on first end 234 of substrate 232 to fix electrode arrangement110 in place. Other connecting mechanisms for securing substrate 232 toreceptacle 125 will be apparent to those skilled in the art ofmechanical connection.

Receptacle 125 may attach to alternating current source 102 via acontinuation of second lead 124 (not shown).

It will be appreciated that various hand-held, impedance-measuringdevices are known in the art, and are commercially available. Hence, thedescription of the known aspects of such a device has been broadlypresented. One of ordinary skill in the art will readily appreciate thatvarious designs are possible. Thus, the instant details of constructionand the arrangement of the components are not intended to limit theapplication of the inventive device.

One aspect of the method of the present invention will now be described,with reference to the logical flow diagram provided in FIG. 7 (allnumbered device components appear in FIG. 5). Using a device such asmoisture-analyzing device 100, an electrode arrangement such aselectrode arrangement 110 is disposed against soft tissue of the innereyelid (step 1). When alternating current source 102 is activated, thesoft tissue between and generally around the electrodes electricallybridges between the electrodes to complete electrical circuit 190. Thealternating current passes from the first electrode to the secondelectrode via the soft tissue, producing an electrical signal (step 2).

Processor or CPU 150 receives this signal, or electrical informationderived from the electrical signal, via circuit 190 (step 3), and thenprocesses the electrical signal, possibly along with other information,to produce an output relating to, or derived from, the parameterassociated with soft tissue of the inner eyelid of the subject (step 4).This eye-moisture correlated output may then be displayed (step 5) bydisplay unit 152.

The output may be in the form of a level of moisture or moisture ratingin the soft tissue of the inner eyelid, or in various other forms. Theoutput may be essential in diagnosing various health conditions of thepatient, and in assessing the severity of various health problems. Also,the output may aid in the matching of interventions and treatments tothe true state of the patient.

Processor 150 may calculate the electrical impedance (Z) based on therelationship:

Z=R+iX

where R is the ohmic resistance and X is the reactance. In the eye, wehave found that the reactance term stems solely from capacitance, hence,

Z=R+iX _(c)

where X_(c) is the capacitance of the circuit between the electrodes.

The capacitance term is non-zero, and may appreciably contribute to theelectrical impedance.

In any event, when processor 150 is provided with the current (I)provided by alternating current source 102, along with a voltage signalfrom circuit 190, the impedance may be calculated from the ratio of thetwo, according to the relationship:

Z=V/I

where V is a voltage associated with the voltage signal. The ratio ofvoltage to current has been found to strongly correlate with tissuemoisture.

In monitoring the moisture of the tissue over the course of time, wesurprisingly found that when the electrode arrangement is provided withthe alternating current, and is disposed against the soft tissue of theinner eyelid, the output signal is largely unaffected by the particulartime that the electrical measurement is made, or by the length of time(at least within 2-10 seconds) that the electrode stick is disposedagainst the soft tissue. The impedance/conductivity measurements may bemade over 10 times, over 20 times, over 50 times, or over 100 times,within the measurement period, which is typically 2-10 seconds, and moretypically, 3.5 to 7 seconds. The processor may thus be configured toprovide an average of the multiple readings, such that the result may beappreciably more reliable than any individual reading. The processor maybe configured to eliminate faulty readings from the average, or toweight the individual results obtained.

Thus, the device and method of the present invention may provide resultsthat are accurate, repeatable, and representative of the state ofmoisture in the outer eye of the subject.

Processor 150 may use the relationship between voltage and current tocompute an absolute tissue moisture, or a relative tissue moisture. Therelative tissue moisture may be rated, by way of example, on a scale of1 to 10, or by comparison to the tissue moistures for a particulargroup, e.g., based on gender.

As used herein in the specification and in the claims section thatfollows, the terms “osmolarity” and “osmolality” are usedinterchangeably. In the extremely weak saline tear solutions, thedifference between the terms is substantially negligible.

As used herein in the specification and in the claims section thatfollows, the term “electrically connected” refers to a physicalconnection between elements that enables an electrical current to flowtherebetween, when the elements are connected to a current sourcedelivering current.

It will be appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, mayalso be provided in combination in a single embodiment. Conversely,various features of the invention, which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable sub-combination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

What is claimed is:
 1. A device for evaluation of a moisturecharacterization parameter associated with moisture of soft tissue on aninner surface of an eyelid of a subject, the device comprising: (a) analternating current source, adapted to connect to a power supply and toproduce an alternating current; (b) an electrode arrangement having atleast a first electrode and a second electrode, said first electrodeelectrically separated from said second electrode by an electricallyinsulating region, said arrangement having an at least semi-rigid regionfixing said electrodes in a spaced-apart manner, said arrangementadapted to contact the soft tissue on the inner surface of the eyelid,said electrodes and said insulating region composed of biocompatiblematerials; and (c) a processor, associated with said electrodearrangement, said first and second electrodes being electricallyconnected to said alternating current source, wherein, when saidelectrode arrangement is provided with said alternating current, and isdisposed against the soft tissue, the soft tissue electrically bridgesbetween said electrodes to form an electrical circuit, such that anelectrical signal is produced by said alternating current passing fromsaid first electrode to said second electrode via the soft tissue, saidprocessor being adapted to receive in-vivo based electrical informationoriginating from said electrical signal, via said circuit, and toproduce an output relating to, or derived from, the moisture parameter,based on said in-vivo electrical information, said processor beingdesigned and configured to compute the moisture parameter in the softtissue, at least partially based on said in-vivo electrical information,and based on an empirical correlation between said in-vivo electricalinformation and said moisture parameter, said empirical correlationincluding an inverse relationship between an electrical impedancederived from said electrical signal or from said in-vivo electricalinformation, and said moisture parameter, such that an increasing levelof moisture of soft tissue on the inner surface of the eyelid iscorrelated with a decreasing of said electrical impedance.
 2. The deviceof claim 1, said moisture parameter being, or including, an eye-moisturecharacterization parameter selected from the group of parametersconsisting of a calculated in-vitro osmolarity, a calculated Schirmer'sTest absorption length, a calculated Meibomian Grading Score, an ocularsurface disease index (OSDI), a corneal and conjunctival stainingresult, and an eye dryness severity value.
 3. The device of claim 1,further comprising an adaptor, electrically connected to saidalternating current source, said adaptor having an engagement mechanismadapted to physically hold a portion of said arrangement and toelectrically connect said arrangement to said current source and to saidprocessor.
 4. The device of claim 3, said engagement mechanism adaptedto releasably and reversibly engage said arrangement.
 5. The device ofclaim 1, said arrangement including, or consisting of, an electrodestick.
 6. The device of claim 4, said engagement mechanism adapted toreleasably and reversibly engage said arrangement, said arrangementincluding, or consisting of, an elongated electrode stick having a firstend adapted to be received by said engagement mechanism, and a secondend having said electrodes.
 7. The device of claim 6, said second endhaving a maximum width of 6.5 mm or 6.3 mm.
 8. The device of claim 6,said second end having a minimum width of 2 mm.
 9. The device of claim6, wherein a maximum distance between said second end of said stick, andan end of said electrodes distal to said second end, is 2.5 mm.
 10. Thedevice of claim 1, further comprising a capacitor, electrically disposedbetween said electrode arrangement and said processor, said capacitorhaving a capacitance to pass an output signal to said processor, whensaid electrical signal is above a pre-defined threshold.
 11. The deviceof claim 3, wherein an end of said arrangement has an attachmentgeometry that is complementary to an attachment geometry of saidengagement mechanism.
 12. The device of claim 1, said electrodes beingdisposed on an at least semi-rigid substrate.
 13. The device of claim12, said electrode arrangement having a thickness, including saidsubstrate, of less than 1.5 mm.
 14. The device of claim 1, furthercomprising a display, electrically associated with said processor, andadapted to display said output.
 15. The device of claim 1, furthercomprising a housing, said processor and said alternating current sourcedisposed within said housing.
 16. The device of claim 1, said processoradapted to calculate said electrical impedance (Z) based on arelationship:Z=R+iX where R is an ohmic resistance of said circuit and X is areactance of said circuit.
 17. The device of claim 16, said reactance(X) consisting substantially solely of a capacitance term (X_(c)).
 18. Amethod comprising: (a) providing the device according to claim 1; (b)disposing a portion of the electrode arrangement on the inner eyelid,against the soft tissue such that the soft tissue electrically bridgesbetween the electrodes to form said electrical circuit; (c) passing saidalternating current from said first electrode to said second electrodevia the soft tissue, to produce said electrical signal; and (d)receiving, by said processor, said electrical information originatingfrom said electrical signal, via said circuit.
 19. The method of claim18, further comprising computing, by said processor, a representation ofthe parameter associated with the moisture of the soft tissue, based onsaid in-vivo electrical information, and based on an empiricalcorrelation between said electrical information and said moistureparameter.
 20. The method of claim 18, said empirical correlationincluding an inverse relationship between said moisture parameter and anelectrical impedance derived from said electrical signal or from saidin-vivo electrical information, such that an increasing level ofmoisture of soft tissue on the inner surface of the eyelid is correlatedwith a decreasing of said electrical impedance.